Phenylcyclohexylpropanolamine derivatives, preparation and therapeutic application thereof

ABSTRACT

The invention relates to compounds of general formula (I):  
                 
         where R 1  represents H or a (C 1 -C 4 )alkyl, —CO(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkylphenyl or —CO-phenyl group, said phenyl optionally being substituted; R 2  represents H, a halogen atom, an —S(O) z (C 1 -C 4 )alkyl group, where z is equal to 0, 1 or 2, an —NHSO 2 (C 1 -C 4 )alkyl group, an —NHSO 2 -phenyl group or an —NHSO 2 —(C 1 -C 4 ) alkylphenyl group, said phenyl optionally being substituted; R 3  represents an —X—R 4  group—in which X represents a bond, an oxygen atom or a —CH 2 — group and R 4  represents H or a —CR 5 R 6 —COOR 7  group, where R 5 , R 6  and R 7  independently represent H or a (C 1 -C 4 )alkyl group—a phenyl group optionally substituted or fused with a dioxolane group, a —CO—NR 8 R 9  group—where R 8  represents H, a (C 1 -C 4 )alkyl group or a (C 1 -C 4 )alkyl(C 1 -C 4 )alkoxy group and R 9  represents a (C 1 -C 4 )alkyl(C 1 -C 4 )alkoxy group, a —(CH 2 ) n -A group, where n is equal to 0, 1, 2, 3 or 4 and where A represents an indolyl group, a fluorenyl group or a phenyl group which is substituted, an optionally substituted —NH-phenyl group or a —CH(R 10 )—(CH 2 ) n —COOR 11  group, where n is 0, 1, 2 or 3 and where R 11  represents H or a (C 1 -C 4 )alkyl group and R 10  represents H, a (C 1 -C 4 ) alkyl group or a —CH 2 -phenyl group, said phenyl optionally being substituted, or a —COOR 12  group, where R 12  represents H or a (C 1 -C 4 )alkyl group; their process of preparation and their therapeutic application.

The present invention relates to phenylcyclohexylpropanolaminederivatives, to their preparation and to their therapeutic application.

A subject-matter of the present invention is compounds corresponding tothe formula (I)

in which:

R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group, a —CO(C₁-C₄)alkylgroup, a (C₁-C₄)alkylphenyl group or a —CO-phenyl group, said phenyloptionally being substituted by one to three groups chosen,independently of one another, from halogen atoms, (C₁-C₄)alkyl groupsand (C₁-C₄)alkoxy groups;

R₂ is chosen from one of the following groups:

-   -   a hydrogen atom,    -   a halogen atom,    -   an —S(O)_(z)(C₁-C₄)alkyl group, where z is equal to 0, 1 or 2,    -   an —NHSO₂(C₁-C₄)alkyl group,    -   an —NHSO₂-phenyl group, or    -   an —NHSO₂—(C₁-C₄)alkylphenyl group,

where said phenyl is optionally substituted by one to three groupschosen, independently of one another, from halogen atoms, (C₁-C₄)alkylgroups and (C₁-C₄)alkoxy groups; and

R₃ is chosen from one of the following groups:

an —X—R₄ group, in which X represents a bond, an oxygen atom or a —CH₂—group and R₄ represents a hydrogen atom or a group of formula—CR₅R₆—COOR₇, where R₅, R₆ and R₇ represent, independently of oneanother, a hydrogen atom or a (C₁-C₄)alkyl group, R₄ not representing,however, a hydrogen atom when X represents a bond,

a phenyl group optionally substituted by one to three groups chosen,independently of one another, from halogen atoms, (C₁-C₄)alkyl groupsand (C₁-C₄)alkoxy groups or fused with a dioxolane group (so as to forma benzodioxolane group), or

a —CO—NR₈R₉ group, in which R₈ represents a hydrogen atom, a(C₁-C₄)alkyl group or a (C₁-C₄)alkyl(C₁-C₄)alkoxy group and R₉ is chosenfrom one of the following groups:

a (C₁-C₄)alkyl(C₁-C₄)alkoxy group,

a group of formula —(CH₂)_(n)-A, where n is equal to 0, 1, 2, 3 or 4 andwhere A represents an indolyl, fluorenyl or phenyl group, where thephenyl group is substituted by one to three groups chosen, independentlyof one another, from halogen atoms, hydroxyl groups and (C₁-C₄) alkylgroups,

an —NH-phenyl group, where the phenyl group is optionally substituted byone to three groups chosen, independently of one another, from halogenatoms, hydroxyl groups and (C₁-C₄) alkyl groups, or

a group of formula —CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n is equal to 0, 1,2 or 3, R₁₁ represents a hydrogen atom or a (C₁-C₄)alkyl group and R₁₀represents:

-   -   a hydrogen atom,    -   a (C₁-C₄)alkyl group,    -   a —COOR₁₂ group, where R₁₂ represents a hydrogen atom or a        (C₁-C₄)alkyl group or    -   a —CH₂-phenyl group, where the phenyl group is optionally        substituted by one to three groups chosen, independently of one        another, from halogen atoms, hydroxyl groups and (C₁-C₄)alkyl        groups.

The compounds of formula (I) can comprise one or more asymmetric carbonatoms. Furthermore, the cyclohexyl group of these compounds exhibits ageometrical asymmetry. The * symbols in the above formula (I) denote thecarbons which can give rise to different geometrical configurations.

The compounds of formula (I) can thus exist in the form of enantiomersor of diastereoisomers. These enantiomers, diastereoisomers and theirmixtures, including racemic mixtures, form part of the invention.

Preference is given in particular to the compounds of formula (I)according to the invention which exhibit the following configuration:

The compounds of formula (I) can exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids but the salts of other acids, for example of use for thepurification or the isolation of the compounds of formula (I) also formpart of the invention.

The compounds of formula (I) can also exist in the form of hydrates orsolvates, namely in the form of combinations or associations with one ormore molecules of water or with a solvent. Such hydrates and solvatesalso form part of the invention.

In the context of the present invention:

the term “a halogen atom” is understood to mean: a fluorine, a chlorine,a bromine or an iodine;

the term “a (C₁-C₄)alkyl group” is understood to mean: a linear orbranched, saturated aliphatic group comprising from 1 to 4 carbon atoms(it being clearly understood that such a group can be only linear whenit comprises less than 3 carbon atoms and that such a group can belinear or branched when it comprises 3 or 4 carbon atoms). Mention maybe made, by way of examples, of the methyl, ethyl, propyl, isopropyl,butyl or isobutyl groups, and the like;

the term “a (C₁-C₄)alkoxy group” is understood to mean: an —O—(C₁-C₄)alkyl radical, where the (C₁-C₄)alkyl group is as defined above;

the term “a (C₁-C₄)alkyl(C₁-C₄)alkoxy group” is understood to mean: aradical of formula (C₁-C₄) alkyl-O—(C₁-C₄) alkyl, where the (C₁-C₄)alkyl group is as defined above; and

the term “a (C₁-C₄)alkylphenyl group” is understood to mean: a group offormula —(CH₂)_(x)-phenyl, where x is between 1 and 4.

Mention may be made, among the compounds of formula (I) which aresubject matters of the invention, of the preferred compounds in which R₁represents a hydrogen atom and/or R₂ represents an —SO₂(C₁-C₄)alkylgroup (such as an —SO₂CH₃ group) or an —NHSO₂(C₁-C₄)alkyl group (such asan —NHSO₂CH₃ group).

Preference is also given, among the compounds of formula (I) which aresubject matters of the invention, to those in which

R₁ represents a hydrogen atom;

and/or R₂ represents an —SO₂(C₁-C₄)alkyl group (such as an —SO₂CH₃group) or an —NHSO₂(C₁-C₄)alkyl group (such as an —NHSO₂CH₃ group);

and/or R₃ is chosen from one of the following groups:

an —X—R₄ group, in which X represents a bond, an oxygen atom or a —CH₂—group and R₄ represents a hydrogen atom or a group of formula—CR₅R₆—COOR₇, where R₅, R₆ and R₇ are as defined above, R₄ notrepresenting, however, a hydrogen atom when X represents a bond or a—CH₂— group,

a phenyl group optionally substituted by one to three groups chosen,independently of one another, from halogen atoms, (C₁-C₄)alkyl groupsand (C₁-C₄)alkoxy groups or fused with a dioxolane group, or

a —CO—NR₈R₉ group, in which R₈ is as defined above and R₉ is chosen fromone of the following groups:

a (C₁-C₄)alkyl(C₁-C₄)alkoxy group,

a group of formula —(CH₂)_(n)-A, where n is equal to 0, 1, 2, 3 or 4 andwhere A represents an indolyl group, a fluorenyl group or a phenyl groupsubstituted by one to three groups independently chosen from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups,

an —NH-phenyl group, where the phenyl group is optionally substituted byone to three groups chosen, independently of one another, from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups, or

a group of formula —CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n is equal to 0, 1,2 or 3, R₁₁ represents a hydrogen atom or a (C₁-C₄) alkyl group and R₁₀represents:

-   -   a hydrogen atom,    -   a (C₁-C₄)alkyl group,    -   a —COOR₁₂ group, where R₁₂ represents a hydrogen atom or a        (C₁-C₄)alkyl group, or    -   a —CH₂-phenyl group, where the phenyl group is optionally        substituted by one to three groups chosen, independently of one        another, from halogen atoms, hydroxyl groups and (C₁-C₄)alkyl        groups.

Mention may also be made of the preferred compounds of formula (I) inwhich:

R₁ represents a hydrogen atom;

and/or R₂ represents an —SO₂(C₁-C₄)alkyl group (such as an —SO₂CH₃group) or an —NHSO₂(C₁-C₄)alkyl group (such as an —NHSO₂CH₃ group);

and/or R₃ represents a —CO—NHR₉ group, in which R₉ is chosen from one ofthe following groups:

a group of formula —(CH₂)_(n)-A, where n is equal to 0, 1, 2, 3 or 4 andwhere A represents an indolyl group, a fluorenyl group or a phenyl groupsubstituted by one to three groups independently chosen from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups,

an —NH-phenyl group, where the phenyl group is optionally substituted byone to three groups chosen, independently of one another, from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups, or

a group of formula —CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n is equal to 0, 1,2 or 3, R₁₁ represents a hydrogen atom or a (C₁-C₄)alkyl group and R₁₀represents:

-   -   a hydrogen atom,    -   a (C₁-C₄)alkyl group,    -   a —COOR₁₂ group, where R₁₂ represents a hydrogen atom or a        (C₁-C₄)alkyl group, or    -   a —CH₂-phenyl group, where the phenyl group is optionally        substituted by one to three groups chosen, independently of one        another, from halogen atoms, hydroxyl groups and (C₁-C₄)alkyl        groups.

In what follows, the term “protective group Pg” is understood to mean agroup which makes it possible, first, to protect a reactive functionalgroup, such as a hydroxyl or an amine, during a synthesis and, secondly,to regenerate the reactive functional group intact at the end of thesynthesis. Examples of protective groups and methods for protecting anddeprotecting are given in “Protective Groups in Organic Synthesis”,Green et al., 2nd edition (John Wiley & Sons Inc. New York).

In accordance with the invention, the compounds of general formula (I),where R₃ is other than a —CO—NR₈R₉ group (that is to say, where R₃represents an —X—R₄ group or a phenyl group optionally substituted orfused with one or more other groups, as defined above), can be preparedaccording to the process described in scheme 1.

According to scheme 1, in a stage (i), the compound of formula (II),where Pg represents a protective group and R represents an electrophilicgroup, is reacted with the epoxide of formula (III), where R₁ and R₂ areas defined above.

The compounds of formula (III) are known in the literature (for examplein the patent application published under the number WO 02/44139) orelse can be prepared by processes analogous to the processes which aredescribed therein. In the case where R₂ can react during this stage (i)or the subsequent stages, it is protected beforehand using protectivegroups well known to a person skilled in the art. Furthermore, when R₁represents a hydrogen atom, it is preferable to protect the hydroxylfunctional group by a protective group in order to increase the yield ofthe reaction. To this end, use may be made of standard protective groupsfor phenol groups, such as methoxyethoxymethyl (MEM),trimethylsilylethoxymethyl (SEM), benzyl, which is optionallysubstituted, or benzoyl.

With regard to the amine of the compound (II), it is partially protectedusing a protective group Pg, such as an optionally substituted benzylgroup (for example a para-methoxybenzyl group) or a methoxyethoxymethyl(MEM) group. It is preferable here to use protective groups which onlypartially protect the reactivity of the amine functional group, that isto say which do not detrimentally affect its nucleophilic nature. Duringstage (i), the partially protected primary amine in the compound (II)can react only with a single molecule of the epoxide (III) and not withtwo molecules, thus preventing the formation of reaction by-products.Stage (i) results in the aminoalcohol of formula (IV). This stage is,for example, carried out in an organic solvent, such as a lower alcohol,for example methanol, ethanol, isopropanol or tert-butanol, or also indimethyl sulfoxide, in a linear or cyclic ether, in an amide, such asdimethylformamide or dimethylacetamide, or also in a mixture of thesesolvents, preferably using at least equimolar amounts of the reactants.The temperature of the reaction is advantageously between ambienttemperature and the reflux temperature of the solvent chosen.

In a stage (ii), the OR group is converted to an R₃ functional group, R₃being as defined above but being other than a —CO—NR₈R₉ group. Forexample, in the case where the OR group represents a triflate functionalgroup, a coupling can be carried out with an arylboronic or aryltinderivative with catalysis by a transition metal, such as palladium, inthe presence of a phosphine, in a solvent, such as toluene,tetrahydrofuran, DME or dimethylformamide, and if necessary in thepresence of a base (for example sodium carbonate) and of water; acompound (V) is then obtained where R₃ is an aryl group, for example aphenyl group optionally substituted or fused with one or more othergroups as defined in the formula (I) of the compounds according to theinvention.

In the case where OR represents an —O—CR₅R₆—COOR₇ group, where R₅ and R₆are as defined in the formula (I) and R₇ represents a (C₁-C₄)alkylgroup, it is possible, during stage (ii), to hydrolyze the esterfunctional group to an acid, in order to obtain a compound (V) in whichR₃=—O—CR₅R₆—COOH, by treatment with a base, for example sodiumhydroxide, in a solvent or a mixture of solvents, such as anethanol/water mixture.

It is clearly understood that, when the OR group in the startingcompound (II) already represents the desired R₃ group, then stage (ii)has no reason to occur. For example, when OR represents a hydroxylgroup, then the desired compound (V) in which R₃═OH is obtained directlyby reaction between the compounds (II) and (III).

The compounds of formula (I) are finally obtained in a stage (iii) afterremoval of the protective groups using techniques known to a personskilled in the art. In particular, when the protective groups are benzylgroups, deprotection is carried out using hydrogen in the presence ofpalladium-on-charcoal in a solvent, such as ethanol. However, in thecase where R₂ represents an —S(O)(C₁-C₄)alkyl group, this stage ofremoval of the protective groups will preferably be avoided and use willpreferably be made, as starting material, of a compound (II) carrying aprimary amine (Pg=H for the compounds (II), (IV) and (V) in scheme 1).

The compounds of formula (II), used as starting materials in the processaccording to scheme 1, can be prepared according to the processpresented in scheme 2.

In scheme 2, the ketone functional group of the compound of formula (VI)is converted, in a stage (iv), to an amine functional group according tomethods well known to a person skilled in the art (for example byreductive amination). This amine is protected using two protectivegroups Pg and Pg′. Pg and Pg′ have different chemical natures, inparticular with regard to their method of deprotection (whichsubsequently makes possible selective deprotection of one or other ofthe protective groups). For example, Pg can be a benzyl group and Pg′ acarbamate functional group. Pg and Pg′ are introduced according tomethods well known to a person skilled in the art (for example byaddition of an acid anhydride or acid chloride for the introduction of acarbamate unit) and generally after the conversion of the ketonefunctional group of the compound (VI) to an amine functional group.

During stage (v), the compound (VIII) is obtained by reacting the phenolfunctional group of the compound (VII) with an electrophile (R group)which can be an acid anhydride, an acid halide or a halogenated alkylderivative. When an acid halide or an acid anhydride (for exampletrifluoromethanesulfonic anhydride) is reacted, the reaction is carriedout in a solvent, such as tetrahydrofuran, a linear ether,dichloromethane or toluene, and in the presence of a base, such astriethylamine, pyridine or diisopropylethylamine. In the case where ahalogenated alkyl derivative (for example ethyl bromoacetate) isreacted, the reaction is carried out in a solvent, such astetrahydrofuran, acetone or dimethylformamide, and in the presence of abase, such as sodium hydride, potassium bicarbonate or sodium hydroxide.

The compound (II) is obtained, in the final stage (vi), by selectivedeprotection of the protective group Pg′ from the cyclohexylamine (VIII)according to methods well known to a person skilled in the art. Forexample, in the case where Pg is a benzyl group and Pg′ is atert-butoxycarbonyl group, deprotection is carried out using a solutionof trifluoroacetic acid in dichloromethane.

Furthermore, the compounds of general formula (I), where R₃ represents a—CO—NR₈R₉ group (R₈ and R₉ being as defined above in connection with theformula (I) of the compounds according to the invention), can beprepared according to the process described in scheme 3.

According to scheme 3, the ketone functional group of the compound offormula (IX) is converted, in a stage (vii), to an amine group accordingto methods well known to a person skilled in the art (for example byreductive amination). The amine (X) is partially protected using aprotective group Pg, such as an optionally substituted benzyl group (forexample a para-methoxybenzyl group) or a methoxyethoxymethyl (MEM)group. It is preferable here to use protective groups which onlypartially protect the reactivity of the amine functional group, that isto say which do not detrimentally affect its nucleophilic nature.However, in the case where R₂ represents an —S(O)(C₁-C₄)alkyl group, usewill preferably be made of a compound (X) carrying a primary amine (Pg=Hfor the compound (X) in scheme 3).

In a stage (viii), the compound of formula (X) is reacted with theepoxide of formula (III) already defined in scheme 1 above. In the casewhere R₂ represents an —S(O)(C₁-C₄)alkyl group, the nitrogen of thecompound (XI) will subsequently be protected with an amino-protectivegroup, such as t-butyloxycarbonyl (BOC) (Pg=BOC in scheme 3 for thecompounds (XI), (XII) and (XIII)), according to methods known to aperson skilled in the art. In the case where R₂ can react during thisstage (viii) or the subsequent stages, it is protected beforehand usingprotective groups well known to a person skilled in the art.Furthermore, when R₁ represents a hydrogen atom, it is preferable toprotect the hydroxyl functional group by a protective group in order toincrease the yield of the reaction, as explained above in connectionwith scheme 1.

During stage (viii), the partially protected primary amine in thecompound (X) can react only with a single molecule of the epoxide (III)and not with two molecules, thus preventing the formation of reactionby-products.

Stage (viii) results in the aminoalcohol of formula (XI). This stage iscarried out, for example, in an organic solvent, such as a loweralcohol, for example methanol, ethanol, isopropanol or tert-butanol, oralso in dimethyl sulfoxide, in a linear or cyclic ether, in an amide,such as dimethylformamide or dimethylacetamide, or also in a mixture ofthese solvents, preferably using at least equimolar amounts of thereactants. The temperature of the reaction is advantageously betweenambient temperature and the reflux temperature of the solvent chosen.

In a stage (ix), the ethyl ester of the compound (XI) is hydrolyzed toan acid (XII) by treatment by a base, for example sodium hydroxide, in asolvent or a mixture of solvents, such as an ethanol/water mixture.

The amide of formula (XIII) is obtained, in a stage (x), by reacting theacid (XII) with an amine of formula HNR₈R₉, in which R₈ and R₉ are asdefined in connection with the formula (I) described above, in thepresence of a coupling agent, for example1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) or benzotriazol-1-yloxy-N,N′-tetramethyluronium tetrafluoroborate(TBTU), and in the presence of a base, such as triethylamine orpyridine, in a solvent, such as dichloromethane, acetonitrile orchloroform. It is also possible to activate the acid functional group ofthe compound (XII) in the form of an acid chloride or of a carbonicanhydride according to techniques known to a person skilled in the art.

The compounds of formula (I) are finally obtained, in a stage (xi),after removal of the protective groups using techniques known to aperson skilled in the art or, if necessary, after conversion of an estergroup to an acid functional group and then removal of the protectivegroups. In particular, when the protective groups are benzyl groups,deprotection is carried out by means of hydrogen in the presence ofpalladium-on-charcoal in a solvent, such as ethanol.

In the case where the compound (XIII) comprises, as R₉ group, an estergroup of formula —CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where R₁₁ represents a(C₁-C₄)alkyl group and R₁₀ is as defined above in connection with thecompounds of formula (I) in accordance with the invention, then thestage of removal of the protective groups is carried out afterconversion of the ester group to an acid functional group.

In scheme 3, it is clearly understood that it is possible to use, asstarting material (IX), an ester other than an ethyl ester, for examplea methyl or propyl ester or any other ester of a lower alkyl.

The compounds of formula (IX), of use in the implementation of theprocess presented in scheme 3, can be prepared according to scheme 4,illustrated by way of example for the preparation of an ethyl ester ascompound (IX)

According to scheme 4, in a stage (xii), the compound of formula (XIV)is condensed with the compound of formula (XV), in which Hal representsa halogen atom, preferably bromine, for example according to the methoddescribed by Meyers et al. in J. Org. Chem., 1974, 39, 2787. Theintermediate alcohol of formula (XVI) thus obtained is converted, in astage (xiii), to an unsaturated compound (XVII), for example using SOCl₂in pyridine, according to the method described by Gonzales-Cameno et al.in Tetrahedron, 1994, 50, 10971, or else using POCl₃, as described, forexample, in Org. Prep. Proced. Int., 1995, 27, 122.

The unsaturated compound (XVII) is subsequently reduced, in a stage(xiv), to a compound (XVIII) according to conventional methods, forexample using hydrogen in the presence of palladium-on-charcoal in asolvent, such as ethanol.

The acetal group of the compound (XVIII) is hydrolyzed, in a stage (xv),analogously to the reaction described by Szantay et al. in Tetrahedron,1996, 52(33), 11053, namely using hydrochloric acid in acetone, andresults in the compound (XIX), which is subsequently hydrolyzed to acompound (IX), in a stage (xvi), according to the method described bySeebach et al. in Synthesis Communications, 1982, 138, or by Nelson etal. in J. Org. Chem., 1994, 59(9), 2577. Alternatively, the compound(XVIII) can be converted directly to the compound (IX) by heating atreflux in ethanol and addition of sulfuric acid, according to the methoddescribed by Degraw et al. in J. Med. Chem., 1992, 35(2), 320, or byTaylor et al. in Heterocycles, 1996, 43(2), 323.

It is clearly understood that a process identical to that presented inscheme 4 could be employed for the preparation of compounds (IX) in theform of esters other than the ethyl ester by hydrolyzing the compound(XVIII) using alcohols carrying alkyl groups other than an ethyl group.

In schemes 1, 2, 3 and 4, the starting compounds and the reactants, whentheir method of preparation is not described, are available commerciallyor are described in the literature or else can be prepared according tomethods which are described therein or which are known to a personskilled in the art.

The following examples describe the preparation of some compounds inaccordance with the invention. These examples are not limiting and onlyillustrate the present invention. The numbers of the compounds given inthe examples refer to those given in the table below, in which thechemical structures and the physical properties of a few compoundsaccording to the invention are illustrated.

Preparation 1:trans-4{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyltrifluoromethanesulfonate (Intermediate Product of Formula (IV) whereR₁=Pg=benzyl, R₂=—NH—SO₂—CH₃ and R=—SO₂CF₃) 1.1:trans-4-[4-(Benzylamino)cyclohexyl]phenol hydrochloride

A solution of 12.2 ml of benzylamine (111 mmol) and of 5.3 g of4-(4′-hydroxyphenyl)-cyclohexanone (27 mmol) in trimethyl orthoformate(100 ml) is heated at 50° C. for 3 h. The solvents are evaporated underreduced pressure and 100 ml of isopropanol and then 1.16 g of sodiumborohydride are added. The reaction mixture is left stirring for 16 h.The solvents are evaporated under reduced pressure and a molar aqueoushydrochloric acid solution is added to pH=1. The precipitate is filteredoff and washed under hot conditions with acetonitrile.trans-4-[4-(Benzylamino)cyclohexyl]phenol hydrochloride is obtained inthe form of a solid (4 g, 48%). [M+H⁺]=282.5

1.2: tert-Butyl trans-benzyl[4-(4-hydroxyphenyl)-cyclohexyl]carbamate

A solution of 13.7 g of trans-4-[4-(benzyl-amino)cyclohexyl]phenolhydrochloride (48.7 mmol) and of 11.69 g of di(tert-butyl) dicarbonate(53.3 mmol) in ethyl acetate (295 ml) is heated at reflux for 4 h. Thesolvents are subsequently evaporated under reduced pressure and thetert-butyl trans-benzyl[4-(4-hydroxyphenyl)cyclohexyl]carbamate isobtained in the form of crystals (12.68 g, 68.2%) after purification onsilica gel (eluent: dichloromethane/methanol 98/2). [M+H⁺]=382.4

1.3: trans-4-{4-[Benzyl(tert-butoxycarbonyl)-amino]cyclohexyl}phenyltrifluoromethanesulfonate

A solution of 12.6 g of tert-butyltrans-benzyl[4-(4-hydroxyphenyl)cyclohexyl]carbamate (33 mmol) and of11.5 ml of 2,6-lutidine (99 mmol) in dichloromethane (125 ml) is stirredat 0° C. 6.1 ml of trifluoromethanesulfonic anhydride are subsequentlyadded and the reaction mixture is left stirring for 1 h 30. Water isadded and the aqueous phase is extracted once with dichloromethane. Theorganic phases are combined and dried over sodium sulfate. The solventsare evaporated under reduced pressure andtrans-4-{4-[benzyl(tert-butoxycarbonyl)amino]-cyclohexyl}phenyltrifluoromethanesulfonate is obtained in the form of crystals (16.43 g,97%) after purification on silica gel (eluent: dichloromethane).[M+H⁺]=514.4

1.4: trans-4-[4-(Benzylamino)cyclohexyl]phenyl trifluoromethanesulfonate

A solution of 16.4 g oftrans-4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}phenyltrifluoromethanesulfonate (32 mmol) in a mixture of trifluoroacetic acid(150 ml) and dichloromethane (900 ml) is stirred for 1 h 30. Thesolvents are evaporated under reduced pressure and then water, ethylacetate and an aqueous ammonia solution are added. The organic phase iswashed once with water and dried over sodium sulfate.trans-4-[4-(Benzylamino)cyclohexyl]-phenyl trifluoromethanesulfonate isobtained in the form of crystals (12.96 g, 98%) after evaporation of thesolvents under reduced pressure. [M+H⁺]=414.2

1.5:trans-4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyltrifluoromethanesulfonate

A mixture of 5.52 g of trans-4-[4-(benzylamino)cyclohexyl]phenyltrifluoromethanesulfonate (13.3 mmol) and of 5 g of4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene(11.2 mmol) in ethanol (72 ml) is brought to reflux for 5 h. The solventis evaporated under reduced pressure andtrans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyltrifluoromethanesulfonate is obtained in the form of an oil (6.94 g,72%) after purification on silica gel (eluent: dichloromethane/methanol98/2). [M+H⁺]=863.4

1.6:trans-4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}phenyltrifluoromethanesulfonate

A solution of 1.4 g oftrans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(tert-butoxy-carbonyl)(methylsulfonyl)amino]phenoxy)-2-hydroxy-propyl)amino]cyclohexyl}phenyltrifluoromethanesulfonate (1.62 mmol) in a mixture of trifluoroaceticacid (5 ml) and of dichloromethane (45 mol) is stirred for 3 h 20. Thesolvents are evaporated under reduced pressure and then water, ethylacetate and an aqueous ammonium solution are added. The organic phase iswashed once with water and dried over sodium sulfate.trans-4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}phenyltrifluoromethanesulfonate is obtained in the form of an oil (1.27 g,98%) after evaporation of the solvents under reduced pressure.[M+H⁺]=763.5.

Preparation 2: Ethyltrans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-phenoxy)acetate(Intermediate Product of Formula (IV) where R₁=Pg=benzyl, R₂=—NH—SO₂—CH₃and R=—CH₂COOEt) 2.1: Ethyltrans-(4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}phenoxy)acetate

A suspension of 3.82 g (10 mmol) of tert-butyltrans-benzyl[4-(4-hydroxyphenyl)-cyclohexyl]carbamate (cf. preparation1.2) and of 0.48 g of 60% sodium hydride (12 mmol) in dimethylformamide(38 ml) is stirred for 25 minutes and then 1.44 ml of ethyl bromoacetate(13 mmol) are added. The reaction is left stirring for 4 h. The reactionmedium is neutralized by the addition of a saturated aqueous ammoniumchloride solution. The solvents are evaporated under reduced pressureand water and dichloromethane are added. The organic phase is washed 5times with water and then dried over magnesium sulfate. Ethyltrans-(4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}phenoxy)acetateis obtained in the form of a white solid (4.68 g, 100%) afterevaporation of the solvents under reduced pressure.

2.2: Ethyl trans-{4-[4-(benzylamino)cyclohexyl]-phenoxy}acetate

A solution of 4.5 g of ethyltrans-(4-{4-[benzyl(tert-butoxycarbonyl)amino]cyclohexyl}-phenoxy)acetate(9.6 mmol) in a mixture of trifluoroacetic acid (30 ml) anddichloromethane (90 ml) is stirred for 2 h. The solvents are evaporatedunder reduced pressure and then water, ethyl acetate and a saturatedaqueous sodium carbonate solution are added. The organic phase is washedonce with water and dried over sodium sulfate. Ethyltrans-{4-[4-(benzylamino)cyclohexyl]phenoxy}acetate is obtained in theform of an oil (3.22 g, 88%) after evaporation of the solvents underreduced pressure. [M+H⁺]=368.3

2.3: Ethyltrans-(4-{4-[Benzyl((2S)-3-({4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetate

A mixture of 3.22 g of ethyltrans-{4-[4-(benzylamino)cyclohexyl]phenoxy}acetate (8.7 mmol) and 5 gof4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene(11.2 mmol) in ethanol (72 ml) is brought to reflux for 40 h. A 3Nsolution of hydrochloric acid in ethanol is added and the reactionmedium is heated at 50° C. for 19 h. The solvents are evaporated underreduced pressure and then water, dichloromethane and a saturated aqueoussodium carbonate solution are added. The aqueous phase is extracted oncewith dichloromethane. The organic phases are combined, washed with waterand then dried over magnesium sulfate. The solvents are evaporated underreduced pressure and ethyltrans-(4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetateis obtained in the form of an oil (2.7 g, 43%) after purification onsilica gel (eluent: ethyl acetate/heptane 30/70 to 50/50 gradient in 40min). [M+H⁺]=717.6

Preparation 3:trans-4-[4-(Benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (Intermediate Product of Formula (XII) where R₁=Pg=benzyl andR₂=—NH—SO₂—CH₃) 3.1: Ethyl trans-4-[4-(benzylamino)cyclohexyl]-benzoate

A solution of 8.51 ml of benzylamine (77.95 mmol) and of 16 g of ethyl4-(cyclohexanone)benzoate (64.96 mmol) in trimethyl orthoformate (192ml) is heated at 50° C. for 18 h. The solvents are evaporated underreduced pressure and 267 ml of ethanol are added. 2.457 g of sodiumborohydride are subsequently added. The reaction mixture is leftstirring for 2 h. The solvents are evaporated under reduced pressure anddichloromethane and water are added. The aqueous phase is extractedthree times with dichloromethane. The organic phases are dried overmagnesium sulfate and concentrated under reduced pressure. Ethyltrans-4-[4-(benzylamino)cyclohexyl]benzoate is obtained in the form ofan oil (14.69 g, 67%) after purification on silica gel (eluent: ethylacetate/ethanol 90/10). [M+H⁺]=282.2

3.2: Ethyltrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoate

A mixture of 818 mg (1.82 mmol) of4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzeneand of 450 mg (1.82 mmol) of ethyltrans-4-[4-(benzyl-amino)cyclohexyl]benzoate in the base form is heatedat reflux in 15 ml of absolute ethanol for 16 h. The mixture is cooled,3 ml of a saturated ethanolic hydrochloric acid solution are addedthereto and the mixture is heated at 50° C. for 6 h. The solvent isevaporated and the residue is taken up with a mixture of 50 ml of asaturated sodium bicarbonate solution and 50 ml of ethyl acetate. Theorganic phase is washed with a saturated aqueous NaCl solution. Theorganic phase is dried and filtered, and the solvent is evaporated underreduced pressure. The crude product is purified by chromatography on acolumn of silica gel, elution being carried out with a methylenechloride/methanol/NH₄OH (95/5/0.5) mixture. The title compound isobtained in the form of a white solid. [M+H⁺]=687.

3.3: trans-4-[4-(Benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}-amino)cyclohexyl]benzoic acid

A mixture of 4.48 g (5.71 mmol) of ethyltrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methyl-sulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)-cyclohexyl]benzoateand of 38 ml of a 1N aqueous sodium hydroxide solution in 114 ml ofethanol is heated overnight at 50° C. The solvents are evaporated, theresidue is taken up in water and a 1N hydrochloric acid solution isgently added to pH=1. The precipitate is filtered off and dried undervacuum. The title compound is thus obtained in the form of a white solid(4.05 g, 94%)

Melting point=160° C.

Preparation 4:trans-4-[4-(Benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxy-propyl}amino)cyclohexyl]benzoicacid (Intermediate Product of Formula (XII) where R₁=Pg=benzyl andR₂=—SO₂—CH₃) 4.1: Ethyltrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoate

This product is obtained by carrying out the preparation as described inpreparation 3.2 above, using ethyltrans-4-[4-(benzylamino)cyclohexyl]benzoate and4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxy-propoxy)benzene,disclosed in patent application WO 99/65895, and without adding theretothe solution of hydrochloric acid in ethanol. [M+H⁺]=672

4.2:trans-4-[4-(Benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)-cyclohexyl]benzoicacid

The preparation is carried out in a similar way to preparation 3.3 abovebut using ethyltrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)-phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoate.8.13 g (95%) of the title compound are thus obtained in the form of awhite solid (melting point=128-130° C.).

EXAMPLE 1trans-N-{5-[((2S)-3-{[4-(1,1′-Biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-hydroxyphenyl}methanesulfonamide(Compound No. 4) 1.1:trans-N-[5-[((2S)-3-{Benzyl[4-(1,1′-biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]methanesulfonamide

A mixture of 0.3 g (0.39 mmol) oftrans-4{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenyltrifluoromethanesulfonate (preparation 1), of 0.143 g of phenylboronicacid (1.76 mmol), of 0.091 g of tetrakis(triphenylphosphine)palladium(0.078 mmol) and of 0.198 g of sodium hydrogencarbonate (3.52 mmol) inethanol (5 ml) and water (2.5 ml) is brought to reflux for 1 hour. Waterand dichloromethane are subsequently added and the reaction mixture isfiltered. The organic phase is dried over magnesium sulfate. Thesolvents are evaporated under reduced pressure andtrans-N-[5-[((2S)-3-{benzyl[4-(1,1′-biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]methanesulfonamideis obtained in the form of a white solid (0.16 g, 60%) afterpurification on silica gel (eluent: heptane/ethyl acetate 95/5 to 50/50gradient in 20 minutes and 50/50 gradient for 15 minutes). [M+H⁺]=691.5

1.2:trans-N-{5-[((2S)-3-{[4-(1,1′-Biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-hydroxyphenyl}methanesulfonamide

A mixture of 0.16 g oftrans-N-[5-[((2S)-3-{benzyl[4-(1,1′-biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]-methanesulfonamide(0.23 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) inethanol (6 ml) is placed under a hydrogen atmosphere and stirred for 4hours. The reaction mixture is filtered through celite. The solvents areevaporated under reduced pressure andtrans-N-{5-[((2S)-3-{[4-(1,1′-biphenyl-4-yl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-hydroxyphenyl}methanesulfonamideis obtained in the form of a white solid (0.08 g, 68%) afterpurification on silica gel (eluent: dichloromethane/methanol, 99/1 to85/15 gradient in 30 minutes).

Melting point=100-110° C.; [M+H⁺]=511.4; ¹H NMR (d₆-DMSO+D₂O, 200 MHz):1.05-1.35 (m, 2H), 1.4-1.6 (m, 2H), 1.7-2 (m, 5H), 2.4-2.8 (m, 3H), 2.85(s, 3H), 3.7-3.85 (m, 3H), 6.52 (dd, 1H), 6.7-6.82 (m, 2H), 7.2-7.65 (m,9H).

EXAMPLE 2trans-N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[4-(4-hydroxyphenyl)cyclohexyl]amino}-propyl)oxy]phenyl}methanesulfonamide(Compound No. 1) 2.1:trans-N-[5-[((2S)-3-{Benzyl[4-(4-hydroxy-phenyl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]methanesulfonamide

A mixture of 1.52 g (3.38 mmol) of4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methyl-sulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzeneand of 1 g (3.55 mmol) of trans-4-[4-(benzylamino)cyclohexyl]-phenol inthe base form is heated at reflux in 20 ml of absolute ethanol for 16 h.The mixture is cooled, 20 ml of a saturated ethanolic hydrochloric acidsolution are added thereto and the mixture is heated at 50° C. for 1 h.The solvent is evaporated and the residue is taken up in a mixture of100 ml of a saturated sodium bicarbonate solution and 100 ml of ethylacetate. The organic phase is washed with a saturated aqueous NaClsolution. The organic phase is dried and filtered, and the solvent isevaporated under reduced pressure. The crude product is purified bychromatography on a column of silica gel, elution being carried out witha heptane/ethyl acetate (55/45) mixture. The title compound is obtainedin the form of a white solid (1.8 g, 84%). [M+H⁺]=631.5

2.2:trans-N-{2-Hydroxy-5-[((2S)-2-hydroxy-3-{[4-(4-hydroxyphenyl)cyclohexyl]amino}propyl)oxy]phenyl}methanesulfonamide

A mixture of 0.8 g (1.26 mmol) oftrans-N-[5-[((2S)-3-{benzyl[4-(4-hydroxyphenyl)cyclohexyl]amino}-2-hydroxypropyl)oxy]-2-(benzyloxy)phenyl]methanesulfonamideand of 0.2 g of 10% palladium-on-charcoal (50% in water) in ethanol (40ml) is placed under hydrogen atmosphere and stirred for 2 h. Thereaction mixture is filtered through celite. The solvents are evaporatedunder reduced pressure andtrans-N-{2-hydroxy-5-[((2S)-2-hydroxy-3-{[4-(4-hydroxyphenyl)-cyclohexyl]amino}propyl)oxy]phenyl}methanesulfonamideis obtained in the form of a white solid (0.24 g, 67%) afterpurification on silica gel (eluent: dichloromethane/methanol, 95/5 to80/20 gradient in 15 min).

Melting point=85-90° C.; [M+H⁺]=451.4; ¹H NMR (d₆-DMSO, 300 MHz): 1.15(dd, 2H), 1.38 (dd, 2H), 1.68-1.8 (m, 2H), 1.85-2 (m, 2H), 2.25-2.52 (m,3H), 2.61 (dd, 1H), 2.75 (dd, 1H), 2.91 (s, 3H), 3.7-3.9 (m, 3H), 6.55(dd, 1H), 6.65 (d, 2H), 6.75-6.8 (m, 2H), 6.95 (d, 2H).

EXAMPLE 3 Ethyltrans-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]-phenoxy}propyl)amino]cyclohexyl}phenoxy)acetate(Compound No. 2)

A mixture of ethyltrans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}phenoxy)acetate(0.26 mmol) and of 0.25 g of 10% palladium-on-charcoal (50% in water) inethanol (16 ml) is placed under hydrogen atmosphere and stirred for 7 h.The reaction mixture is filtered through celite. The solvents areevaporated under reduced pressure and ethyltrans-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methyl-sulfonyl)amino]phenoxy}propyl)amino]cyclohexyl}-phenoxy)acetateis obtained in the form of a white solid (0.08 g, 54%) afterpurification on silica gel (eluent: dichloromethane/methanol, 99/1 to85/15 gradient in 30 min).

Melting point=60-70° C.; [M+H⁺]=537.6; ¹H NMR (d₆-DMSO+D₂O, 200 MHz):1.1-1.5 (m, 4H), 1.2 (t, 3H), 1.65-1.8 (m, 2H), 1.85-2 (m, 2H), 2.3-2.85(m, 4H), 2.93 (s, 3H), 3.7-3.9 (m, 3H), 4.18 (q, 2H), 4.7 (s, 2H), 6.55(dd, 1H), 6.7-6.85 (m, 4H), 7.08 (d, 2H)

EXAMPLE 4trans-(4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}phenoxy)aceticacid (Compound No. 3) 4.1:trans-(4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]-cyclohexyl}phenoxy)aceticacid

A mixture of 0.36 g of ethyltrans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-phenoxy)acetate(0.49 mmol) and of 6 ml of a molar aqueous sodium hydroxide solution inethanol (10 ml) is heated at 45° C. for 22 h. The solvents aresubsequently evaporated under reduced pressure and water is added. Amolar aqueous hydrochloric acid solution is subsequently added to pH=1.The title product is obtained in the form of a white solid (0.3 g, 89%)after filtration and drying under vacuum. {M+H⁺]=689.7

4.2:trans-(4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]cyclohexyl}phenoxy)aceticacid

A mixture of 0.3 g oftrans-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-phenoxy)aceticacid (0.44 mmol) and of 0.20 g of 10% palladium-on-charcoal (50% inwater) in a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) isplaced under a hydrogen atmosphere and stirred for 4 h. The reactionmixture is filtered through celite. The solvents are evaporated underreduced pressure andtrans-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methyl-sulfonyl)amino]phenoxy}propyl)amino]cyclohexyl}-phenoxy)aceticacid is obtained in the form of a white solid (0.07 g, 32%) afterpurification on C₁₈-grafted silica (eluent: water/acetonitrile, 95/5 to5/95 gradient in 15 min).

Melting point=160-170° C.; [M+H⁺]=509.6; ¹H NMR (d₆-DMSO+D₂O, 200 MHz):1.1-1.45 (m, 4H), 1.6-2 (m, 4H), 2.1-2.25 (m, 1H), 2.6-3.1 (m, 4H), 2.95(s, 3H), 3.75-3.9 (m, 2H), 4-4.15 (m, 1H), 4.28 (s, 2H), 6.55-6.82 (m,5H), 7.05 (d, 2H).

EXAMPLE 5 Ethyltrans-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]-phenoxy}propyl)amino]cyclohexyl}benzoyl)-L-valinate(Compound No. 13) 5.1: Ethyltrans-(2S)-2-[(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoyl)amino]-3-methylbutanoate

A solution of 0.3 g (0.45 mmol) oftrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy]-2-hydroxypropyl}amino)cyclohexylbenzoicacid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole,of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, of 0.19 ml of triethylamine and of 0.165 g (0.91 mmol) ofL-valine ethyl ester hydrochloride in 5 ml of dichloromethane is stirredfor 24 h. The solvents are evaporated under reduced pressure.Dichloromethane and water are added and the organic phase is washedthree times with water. The organic phases are dried over magnesiumsulfate and concentrated under reduced pressure. Ethyltrans-(2S)-2-[(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methyl-sulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]-cyclohexyl}benzoyl)amino]-3-methylbutanoateis obtained in the form of a yellow oil (0.35 g, 98%). {M+H⁺]=786

5.2: Ethyltrans-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}benzoyl)-L-valinate

A suspension of 1.35 g (0.35 mmol) of ethyltrans-(2S)-2-[(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}benzoyl)amino]-3-methylbutanoateand of 0.177 g of palladium-on-charcoal (10% Pd, 50% in water) in 15 mlof ethanol is placed under hydrogen atmosphere and stirred for 3 h. Thecatalyst is subsequently filtered off and the solvents are evaporatedunder reduced pressure. The title compound is obtained in the form of awhite solid (0.138 g, 44%) after purification on silica gel (eluent:dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradientin 30 min).

Melting point=65-75° C.; ¹H NMR (d₆-DMSO+D₂O, 200 MHz): 0.92 (t, 3H),1.1-1.35 (m, 8H), 1.35-1.6 (m, 2H), 1.7-2.25 (m, 5H), 2.4-2.8 (m, 4H),2.92 (s, 3H), 3.6-3.9 (m, 3H), 4-4.2 (m, 2H), 4.25 (t, 1H), 6.6 (dd,1H), 6.68-6.8 (m, 2H), 7.32 (d, 2H), 7.78 (d, 2H).

EXAMPLE 6trans-N-(4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}benzoyl)-L-phenylalanine(Compound No. 19) 6.1: Ethyltrans-N-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoyl)-L-phenylalaninate

A solution of 0.3 g (0.45 mmol) oftrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole,of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, of 0.19 ml of triethylamine and of 0.165 g (0.91 mmol) ofL-phenylalanine ethyl ester hydrochloride in 5 ml of dichloromethane isstirred for 24 h. The solvents are evaporated under reduced pressure.Dichloromethane and water are added and the organic phase is washedthree times with water. The organic phases are dried over magnesiumsulfate and concentrated under reduced pressure. The product is obtainedin the form of a white solid (0.350 g, 92%) after purification on silicagel (eluent: dichloromethane/methanol 100/00 to 90/10 gradient in 35min). [M+H⁺]=835

6.2:trans-N-(4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}benzoyl)-L-phenylalanine

A mixture of 0.35 g of ethyltrans-N-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}benzoyl)-L-phenylalaninate(0.42 mmol) and of 1.7 ml of a molar aqueous sodium hydroxide solutionin ethanol (9.3 ml) is heated at 45° C. for 3 h. The solvents aresubsequently evaporated under reduced pressure and water is added. Amolar aqueous hydrochloric acid solution is subsequently added to pH=1.The title product is obtained in the form of a white solid (0.2 g, 59%)after filtration and drying under vacuum [M+H⁺]=807.

6.3:trans-N-(4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}benzoyl)-L-phenylalanine

A mixture of 0.2 g oftrans-N-(4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-benzoyl)-L-phenylalanine(0.248 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) inethanol (15 ml) is placed under hydrogen atmosphere and stirred for 3 h.The reaction mixture is filtered through celite. The solvents areevaporated under reduced pressure andtrans-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}benzoyl)-L-phenylalanineis obtained in the form of a white solid (0.049 g, 31%) afterpurification on C₁₈-grafted silica (eluent: water/acetonitrile, 95/5 to5/95 gradient in 15 min).

Melting point>230° C.; [M+H⁺]=626.4; ¹H NMR (d₆-DMSO+D₂O, 200 MHz):1.1-1.65 (m, 6H), 1.9-2.1 (m, 2H), 2.2-2.38 (m, 1H), 2.7-3.3 (m, 4H),2.92 (s, 3H), 3.75-3.9 (m, 3H), 4-4.2 (m, 1H), 4.25-4.4 (m, 1H), 6.65(dd, 1H), 6.75-6.9 (m, 2H), 7-7.3 (m, 7H), 7.68 (d, 2H).

EXAMPLE 7trans-4-[4-({(2S)-2-Hydroxy-3-[4-hydroxy-3-(methylsulfonyl)phenoxy]propyl}amino)-cyclohexyl]-N′-phenylbenzohydrazide(Compound No. 26) 7.1:trans-4-[4-(Benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)-cyclohexyl]-N′-phenylbenzohydrazide

A solution of 0.3 g (0.441 mmol) oftrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)-phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (preparation 4), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole,of 0.169 g (0.88 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, of 0.184 ml of triethylamine and of 0.095 g (0.88 mmol)of phenylhydrazine in a mixture of 4 ml of dichloromethane and 0.8 ml ofacetonitrile is stirred for 48 hours. The solvents are evaporated underreduced pressure. Dichloromethane and water are added and the organicphase is washed three times with water. The organic phases are driedover magnesium sulfate and concentrated under reduced pressure. Theproduct is obtained in the form of a white solid (0.166 g, 50%) afterpurification on silica gel (eluent: heptane/ethyl acetate 60/40 for 10min, 60/40 to 40/60 in 10 min, then 40/60 for 20 min gradient).[M+H⁺]=734.7

7.2:trans-4-[4-({(2S)-2-Hydroxy-3-[4-hydroxy-3-(methylsulfonyl)phenoxy]propyl}amino)cyclohexyl]-N′-phenylbenzohydrazide

A mixture or 0.166 g oftrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)-phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N′-phenylbenzohydrazide(0.226 mmol) and of 0.1 g of 10% palladium-on-charcoal (50% in water) ina mixture of ethanol (3.9 ml) and tetrahydrofuran (2.93 ml) is placedunder hydrogen atmosphere and stirred for 48 h. The catalyst issubsequently filtered off and the solvents are evaporated under reducedpressure. The title compound is obtained in the form of a white solid(0.02 g, 16%) after purification on silica gel (eluent:dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradientin 30 min).

Melting point=125° C.; [M+H⁺]=554; ¹H NMR (d₆-DMSO, 200 MHz): 1.0-1.6(m, 4H), 1.7-2.1 (m, 4H), 2.35-2.8 (m, 4H), 2.7-3.3 (m, 4H), 3.2 (s,3H), 3.7-3.95 (m, 3H), 4-4.2 (m, 1H), 4.25-4.4 (m, 1H), 6.65 (dd, 1H),6.6-7.4 (m, 9H), 7.75-7.9 (m, 3H)

EXAMPLE 8trans-N-(4-Fluorobenzyl)-4-[4-({(2S)-2-hydroxy-3-[4-hydroxy-3-(methylsulfonyl)phenoxy]propyl}amino)cyclohexyl]benzamide(Compound No. 25) 8.1:trans-4-[4-(Benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N-(4-fluorobenzyl)benzamide

A solution of 0.3 g (0.441 mmol) oftrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)-phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (preparation 4), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole,of 0.169 g (0.88 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, of 0.184 ml of triethylamine and of 0.11 g (0.88 mmol) of4-fluorobenzylamine in a mixture of 4 ml of dichloromethane and 0.8 mlof acetonitrile is stirred for 48 h. The solvents are evaporated underreduced pressure. Dichloromethane and water are added and the organicphase is washed three times with water. The organic phases are driedover magnesium sulfate and concentrated under reduced pressure. Theproduct is obtained in the form of a white solid (0.232 g, 70%) afterpurification on silica gel (eluent: heptane/ethyl acetate 60/40 for 10min, 60/40 to 40/60 in 10 min and then 40/60 for 20 min gradient).[M+H⁺]=751.5

8.2:trans-N-(4-Fluorobenzyl)-4-[4-({(2S)-2-hydroxy-3-[4-hydroxy-3-(methylsulfonyl)phenoxy]propyl}-amino)cyclohexyl]benzamide

A mixture of 0.166 g oftrans-4-[4-(benzyl-{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]-N-(4-fluorobenzyl)-benzamide(0.226 mmol) and of 0.117 g of 10% palladium-on-charcoal (50% in water)in a mixture of ethanol (5.3 ml) and tetrahydrofuran (4.02 ml) is placedunder a hydrogen atmosphere and stirred for 48 hours. The catalyst issubsequently filtered off and the solvents are evaporated under reducedpressure. The title compound is obtained in the form of a white solid(0.92 g, 52%) after purification on silica gel (eluent:dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradientin 30 min).

Melting point 110° C.; [M+H⁺]=571; ¹H NMR (d₆-DMSO, 500 MHz): 1.12-1.2(m, 2H), 1.4-1.5 (m, 2H), 1.7-1.8 (m, 2H), 1.9-2 (m, 2H), 2.45-2.55 (m,2H), 2.6-2.68 (m, 1H), 2.7-2.8 (m, 1H), 3.22 (s, 3H), 3.75-3.95 (m, 3H),4.4 (s, 2H), 6.88 (dd, 1H), 7.08-7.2 (m, 4H), 7.28-7.3 (m, 3H), 7.74 (d,2H).

EXAMPLE 9trans-4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}-N-[2-(1H-indol-3-yl)ethyl]benzamide(Compound No. 29) 9.1:trans-4-{4-[Benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)-amino]cyclohexyl}-N-[2-(1H-indol-3-yl)ethyl]benzamide

A solution of 0.3 g (0.45 mmol) oftrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (preparation 3), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole,of 0.175 g (0.91 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,of 0.19 ml of triethylamine and of 0.138 g (0.86 mmol) of tryptamine ina mixture of 4 ml of dichloromethane and 0.8 ml of acetonitrile isstirred for 24 h. The solvents are evaporated under reduced pressure.Dichloromethane and water are added and the organic phase is washedthree times with water. The organic phases are dried over magnesiumsulfate and concentrated under reduced pressure. The title compound isobtained in the form of a white solid (0.246 g, 58%) after purificationon silica gel (eluent: heptane/ethyl acetate 60/40 for 10 min, 60/40 to40/60 in 10 min and then 40/60 for 20 min gradient). [M+H⁺]=801.6

9.2:trans-4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]cyclohexyl}-N-[2-(1H-indol-3-yl)ethyl]benzamide

A suspension of 0.246 g (0.3 mmol) oftrans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)-amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}-N-[2-(1H-indol-3-yl)ethyl]benzamideand of 0.332 g of palladium-on-charcoal (10% Pd, 50% in water) in amixture of 5.4 ml of ethanol and 4 ml of tetrahydrofuran is placed underhydrogen atmosphere and is stirred for 3 h. The catalyst is subsequentlyfiltered off and the solvents are evaporated under reduced pressure. Thetitle compound is obtained in the form of a white solid (0.076 g, 40%)after purification on silica gel (eluent:dichloromethane/methanol/aqueous ammonia 99/1/0.1 to 85/15/1.5 gradientin 30 min).

Melting point=125° C.; [M+H⁺]=621; ¹H NMR (d₆-DMSO, 200 MHz): 1-1.2 (m,2H), 1.3-1.55 (m, 2H), 1.7-2 (m, 4H), 2.4-3 (m, 6H), 2.9 (s, 3H),3.4-3.6 (m, 2H), 3.7-3.8 (m, 1H), 3.8-3.95 (m, 3H), 6.6 (dd, 1H),6.7-6.85 (m, 2H), 6.9-7.2 (m, 3H), 7.25-7.4 (m, 3H), 7.55 (d, 1H), 7.75(d, 2H), 8.4-8.5 (m, 1H).

EXAMPLE 10 Ethyltrans-2-{4-[4-({(2S)-3-[3-(butylsulfinyl)-4-hydroxyphenoxy]-2-hydroxypropyl}-amino)cyclohexyl]phenoxy}-2,2-dimethylacetate(Compound No. 34) 10.1: Ethyltrans-2-[4-(4-aminocyclohexyl)-phenoxy]-2,2-dimethylacetatehydrochloride

A mixture of 1.9 g of ethyltrans-2-{4-[4-(benzylamino)cyclohexyl]phenoxy}-2,2-dimethylacetate inthe base form (4.8 mmol) and of 0.1 g of 10% palladium-on-charcoal inethanol (75 ml) is placed under hydrogen atmosphere at 40° C. andstirred for 7 h. The reaction mixture is filtered through celite. Thesolvent is evaporated under reduced pressure and ethyltrans-2-[4-(4-aminocyclohexyl)phenoxy]-2,2-dimethylacetate is obtained(0.660 g) in the form of a yellow oil which is dissolved in ethanol (5ml). The solution is acidified with a solution (9N) of HCl in ethanoland the solid thus obtained is filtered off (0.530 g, 72%). Meltingpoint: 240-242.

10.2: Ethyltrans-2-{4-[4-({(2S)-3-[4-(benzyloxy)-3-(butylsulfinyl)phenoxy]-2-hydroxypropyl}amino)-cyclohexyl]phenoxy}-2,2-dimethylacetate

A mixture of 0.742 g of(2S)-2-{[4-(benzyloxy)-3-(butylsulfinyl)phenoxy]methyl}oxirane (obtainedby analogy with the method disclosed in WO 99/65895 but starting fromthe butyl sulfoxide instead of the methyl sulfoxide and using(S)-(+)-glycidyl nosylate; [α]_(D)=+1.9 (c=1%, MeOH)) (2.06 mmol) and of0.666 g of ethyltrans-2-[4-(4-aminocyclohexyl)phenoxy]-2,2-dimethylacetate hydrochloride(2.18 mmol) in ethanol (25 ml) is heated to reflux overnight. Thesolvent is evaporated under reduced pressure and the product obtained ispurified by flash chromatography, elution being carried out with amethylene chloride/methanol/aqueous ammonia (95/5/0.5) mixture. Thetitle product is obtained in the form of a yellow oil (0.730 g, 53%).

10.3: Ethyltrans-2-{4-[4-({(2S)-3-[3-(butyl-sulfinyl)-4-hydroxyphenoxy]-2-hydroxypropyl}amino)-cyclohexyl]phenoxy}-2,2-dimethylacetate

A solution of 0.720 g of ethyltrans-2-{4-[4-({(2S)-3-[4-(benzyloxy)-3-(butylsulfinyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]phenoxy}-2,2-dimethylacetate(1.08 mmol) in trifluoroacetic acid (12 ml) is heated at 60° C. for 3hours. The solvent is evaporated and the residue is treated with asodium bicarbonate solution and ethyl acetate. The organic phase isseparated, dried, filtered and evaporated under vacuum. The product thusobtained is purified by flash chromatography, elution being carried outwith a methylene chloride/methanol/aqueous ammonia (9/1/0.1) mixture.The title product is obtained in the form of a solid (0.31 g, 50%).

Melting point=58-60° C.; [M+H⁺]=576; ¹H NMR (d₆-DMSO, 313K): 0.86 (t,3H, J=7 Hz), 1.17 (t, 3H, J=7 Hz), 1.05-1.24 (m, 2H), 1.27-1.46 (m, 2H),1.49 (s, 6H), 1.60-1.72 (m, 1H), 1.77 (bd, 2H, J=13 Hz), 1.96 (bd, 2H,J=13 Hz), 2.30-2.47 (m, 2H), 2.58-2.83 (m, 3H), 2.93-3.09 (m, 1H),3.74-3.89 (m, 2H), 3.89-3.98 (m, 1H), 4.16 (q, 2H, J=7 Hz), 6.71 (m,2H), 6.81 (d, 1H, J=9 Hz), 6.92 (dd, 1H, Ja=9 Hz, Jb=3 Hz); 7.07 (d, 1H,J=3 Hz); 7.10 (m, 2H).

The chemical structures and the physical properties of a few compoundsaccording to the invention are illustrated in the following table. Inthis table:

in the “salt” column, “-” represents a compound in the free base form,

Me, Et, iPr, nBu, iBu, Ph and Bn respectively represent the methyl,ethyl, isopropyl, butyl, isobutyl, phenyl and benzyl groups. TABLE (I)

Melting point No. R₁ R₂ R₃ Salt (° C.) 1 H —NHSO₂CH₃ —OH — 85-90 2 H—NHSO₂CH₃

— 60-70 3 H —NHSO₂CH₃

— 160-170 4 H —NHSO₂CH₃

— 100-110 5 H —NHSO₂CH₃

— 90-95 6 H —NHSO₂CH₃

—  95-100 7 H —NHSO₂CH₃

— 140-150 8 H —NHSO₂CH₃

— 105-110 9 H —NHSO₂CH₃

— 120-125 10 H —NHSO₂CH₃

— 165-175 11 H —NHSO₂CH₃

— 215-220 12 H —NHSO₂CH₃

— 64-69 13 H —NHSO₂CH₃

— 65-75 14 H —NHSO₂CH₃

— 65-80 15 H —NHSO₂CH₃

— 73-83 16 H —NHSO₂CH₃

— 70-80 17 H —NHSO₂CH₃

— 150-180 18 H —NHSO₂CH₃

— >250 19 H —NHSO₂CH₃

— >230 20 H —NHSO₂CH₃

— 170-210 21 H —NHSO₂CH₃

pamoate 110-150 22 H —NHSO₂CH₃

— 55-65 23 H —NHSO₂CH₃

— 160-200 24 H —NHSO₂CH₃

— 75-85 25 H —SO₂CH₃

— 110 26 H —SO₂CH₃

— 125 27 H —SO₂CH₃

— 125 28 H —SO₂CH₃

— 115 29 H —NHSO₂CH₃

— 125 30 H —SO₂CH₃

— 141 31 H —SO₂CH₃

—  80 32 H —NHSO₂CH₃

— 45-48 33 H —NHSO₂Ph

— 72-74 34 H —SO(nBu)

— 58-60 35 H —SO(nBu)

— 76-78

The compounds according to the invention have formed the subject ofpharmacological tests which make it possible to determine their agonistactivity effect with regard to β₃ receptors.

The agonist activity with regard to β₃ receptors (reflected byproduction of cAMP induced by the test compound) was studied usingmembrane preparations from SKNMC cells (human neuroblastoma cells) inthe presence of selective β₁ and β₂ antagonists (CGP20712 and ICI118551,both at a concentration of 10⁻⁶M). The activity of the compoundsaccording to the invention (pKa) is greater than or equal to 6.0 (it isgenerally between 6.0 and 7.6). Their effectiveness is greater than orequal to 60% and is generally within the range from 60 to 90%.

The activities of the compounds according to the invention toward β₁ andβ₂ receptors were studied on the auricle and on the trachea,respectively, of guinea-pigs. The agonist and antagonist activities weremeasured. It was thus found that the compounds according to theinvention are selective toward β₃ receptors: specifically, they are atleast 50 times more active toward β₃ receptors than toward β₁ or β₂receptors.

The compounds according to the invention can thus be used for thepreparation of medicaments intended in particular for the treatment ofdiseases in which β₃ receptors are implicated. More particularly, thecompounds according to the invention can be used as medicaments with aβ₃ agonist action.

Thus, according to another of its aspects, a subject matter of theinvention is a medicament which comprises a compound of formula (I), oran addition salt of the latter with a pharmaceutically acceptable acid,or also a hydrate or a solvate of the compound of formula (I).

Examples of diseases in which β₃ receptors are implicated areextensively described in the literature. The compounds of formula (I),and their pharmaceutically acceptable salts, or hydrates or solvates ofthese compounds, can thus be indicated for the treatment ofgastrointestinal diseases, such as inflammatory diseases of theintestine, for example irritable bowel syndrome (IBS) or inflammatorybowel disease (IBD), as modulators of intestinal motricity, aslipolytics, antiobesity agents, antidiabetics, antiglaucoma agents orcicatrizants, as inhibitors of uterine contractions, as tocolytics forpreventing or delaying premature labor, and for the treatment and/orprophylaxis of dysmenorrhea. In addition, the compounds of formula (I),and their pharmaceutically acceptable salts, or hydrates or solvates ofthese compounds, can be used in the treatment of certain diseases of thecentral nervous system, for example as psychotropics or antidepressants,and for certain disorders of the urinary system, such as urinaryincontinence.

The present invention, according to another of its aspects, also relatesto a method for the treatment of the pathologies indicated above whichcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts, or a hydrate or solvate of this compound.

The present invention also relates to pharmaceutical compositionscomprising, as active principle, at least one compound according to theinvention. These pharmaceutical compositions comprise an effective doseof a compound according to the invention, or a pharmaceuticallyacceptable salt, a hydrate or solvate of said compound, and at least onepharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical form and themethod of administration desired, from the usual excipients which areknown to a person skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its optional salt, solvate orhydrate, can be administered in a unit administration form, as a mixturewith conventional pharmaceutical excipients, to animals and to man forthe prophylaxis or the treatment of the above disorders or diseases.

The appropriate unit administration forms comprise oral forms, such astablets, soft or hard gelatin capsules, powders, granules and solutionsor suspensions to be taken orally, sublingual, buccal, intratracheal,intraocular or intranasal administration forms, inhalationadministration forms, topical, transdermal, subcutaneous, intramuscularor intravenous administration forms, rectal administration forms andimplants. For topical application, use may be made of the compoundsaccording to the invention in creams, gels, ointments or lotions.

The dose of active principle administered by is between 0.01 and 20 mgper kilo of body weight of the mammal to be treated, preferably between0.1 and 10 mg/kg. In man, the dose can vary from 0.5 mg to 1500 mg perday, for example from 2.5 to 500 mg, according to the age of the subjectto be treated, the type of treatment (prophylactic or curative) and theseriousness of the condition. The compounds of formula (I) are generallyadministered in a unit dosage form of 0.1 to 500 mg, preferably of 0.5to 100 mg, of active principle, between one and five times daily.

There may be specific cases where higher or lower dosages areappropriate; such dosages do not depart from the scope of the invention.According to the usual practice, the dosage appropriate to each patientis determined by the physician according to the method ofadministration, the weight and the response of said patient.

1. A compound corresponding to the formula (I)

in which: R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group, a—CO(C₁-C₄)alkyl group, a (C₁-C₄)alkylphenyl group or a —CO-phenyl group,said phenyl optionally being substituted by one to three groups chosen,independently of one another, from halogen atoms, (C₁-C₄)alkyl groupsand (C₁-C₄)alkoxy groups; R₂ is chosen from one of the following groups:a hydrogen atom, a halogen atom, an —S(O)_(z)(C₁-C₄)alkyl group, where zis equal to 0, 1 or 2, an —NHSO₂(C₁-C₄)alkyl group, an —NHSO₂-phenylgroup, or an —NHSO₂—(C₁-C₄)alkylphenyl group, where said phenyl isoptionally substituted by one to three groups chosen, independently ofone another, from halogen atoms, (C₁-C₄)alkyl groups and (C₁-C₄)alkoxygroups; and R₃ is chosen from one of the following groups: an —X—R₄group, in which X represents a bond, an oxygen atom or a —CH₂— group andR₄ represents a hydrogen atom or a group of formula —CR₅R₆—COOR₇, whereR₅, R₆ and R₇ represent, independently of one another, a hydrogen atomor a (C₁-C₄)alkyl group, R₄ not representing, however, a hydrogen atomwhen X represents a bond, a phenyl group optionally substituted by oneto three groups chosen, independently of one another, from halogenatoms, (C₁-C₄)alkyl groups and (C₁-C₄)alkoxy groups or fused with adioxolane group, or a —CO—NR₈R₉ group, in which R₈ represents a hydrogenatom, a (C₁-C₄)alkyl group or a (C₁-C₄)alkyl(C₁-C₄)alkoxy group and R₉is chosen from one of the following groups: a (C₁-C₄)alkyl(C₁-C₄)alkoxygroup, a group of formula —(CH₂)_(n)-A, where n is equal to 0, 1, 2, 3or 4 and where A represents an indolyl, fluorenyl or phenyl group, wherethe phenyl group is substituted by one to three groups independentlychosen from halogen atoms, hydroxyl groups and (C₁-C₄)alkyl groups, an—NH-phenyl group, where the phenyl group is optionally substituted byone to three groups chosen, independently of one another, from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups, or a group of formula—CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n is equal to 0, 1, 2 or 3, R₁₁represents a hydrogen atom or a (C₁-C₄)alkyl group and R₁₀ represents: ahydrogen atom, a (C₁-C₄)alkyl group, a —COOR₁₂ group, where R₁₂represents a hydrogen atom or a (C₁-C₄)alkyl group, or a —CH₂-phenylgroup, where the phenyl group is optionally substituted by one to threegroups chosen, independently of one another, from halogen atoms,hydroxyl groups and (C₁-C₄)alkyl groups; in the form of the base or ofaddition salts with acids, and in the form of hydrates or of solvates.2. The compound of formula (I) as claimed in claim 1 wherein R₁represents a hydrogen atom, in the form of the base or of addition saltswith acids, and in the form of hydrates or of solvates.
 3. The compoundof formula (I) as claimed in claim 1 wherein R₂ represents an—SO₂(C₁-C₄)alkyl group or an —NHSO₂(C₁-C₄)alkyl group, in the form ofthe base or of addition salts with acids, and in the form of hydrates orof solvates.
 4. The compound as claimed in claim 1 wherein R₃ is chosenfrom one of the following groups: an —X—R₄ group, in which X and R₄ areas defined in claim 1, R₄ not representing, however, a hydrogen atomwhen X represents a bond or a —CH₂— group, a phenyl group optionallysubstituted by one to three groups chosen, independently of one another,from halogen atoms, (C₁-C₄)alkyl groups and (C₁-C₄)alkoxy groups orfused with a dioxolane group, or a —CO—NR₈R₉ group, in which R₈ is asdefined in claim 1 and R₉ is chosen from one of the following groups: a(C₁-C₄)alkyl(C₁-C₄)alkoxy group, a group of formula —(CH₂)_(n)-A, wheren is equal to 0, 1, 2, 3 or 4 and where A represents an indolyl group, afluorenyl group or a phenyl group substituted by one to three groupsindependently chosen from halogen atoms, hydroxyl groups and(C₁-C₄)alkyl groups, an —NH-phenyl group, where the phenyl group isoptionally substituted by one to three groups chosen, independently ofone another, from halogen atoms, hydroxyl groups and (C₁-C₄)alkylgroups, or a group of formula —CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n isequal to 0, 1, 2 or 3 and where R₁₀ and R₁ are as defined in claim 1; inthe form of the base or of addition salts with acids, and in the form ofhydrates or of solvates.
 5. The compound as claimed in claim 4 whereinR₃ represents a —CO—NHR₉ group, in which R₉ is chosen from one of thefollowing groups: a group of formula —(CH₂)_(n)-A, where n is equal to0, 1, 2, 3 or 4 and where A represents an indolyl group, a fluorenylgroup or a phenyl group substituted by one to three groups independentlychosen from halogen atoms, hydroxyl groups and (C₁-C₄)alkyl groups, an—NH-phenyl group, where the phenyl group is optionally substituted byone to three groups chosen, independently of one another, from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups, or a group of formula—CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n is equal to 0, 1, 2 or 3 and whereR₁₀ and R₁₁ are as defined in claim 1; in the form of the base or ofaddition salts with acids, and in the form of hydrates or of solvates.6. A process for the preparation of the compound of formula (I) asclaimed in claim 1 in which R₃ is other than a —CO—NR₈R₉ group, whereina compound of formula (II), where R represents an electrophilic groupand Pg represents a protective group, is reacted with an epoxide offormula (III), where R₁ and R₂ are as defined in any one of claims 1 to3:

in order to obtain a compound of formula (IV):

which is converted to a compound of formula (V), in which R₃ is asdefined in any one of claims 1 to 4 but is other than a —CO—NR₈R₉ group:

from which the protective groups are subsequently removed.
 7. A processfor the preparation of the compound of formula (I) as claimed in claim 1in which R₃ represents a —CO—NR₈R₉ group, wherein the compound offormula (XII):

where R₁ and R₂ are as defined in any one of claims 1 to 3 and Pgrepresents a protective group, is reacted with an amine of formulaHNR₈R₉, in which R₈ and R₉ are as defined in any one of claims 1 to 5,and then in that the protective groups are removed from the product thusobtained.
 8. (canceled)
 9. A pharmaceutical composition comprising acompound of formula (I) as claimed in claim 1 or a pharmaceuticallyacceptable salt, a hydrate or a solvate of this compound, and at leastone pharmaceutically acceptable excipient.
 10. A method for thetreatment of diseases in which β₃ receptors are implicated whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 1. 11. A methodaccording to claim 10 for the treatment of gastrointestinal diseases,such as inflammatory diseases of the intestine, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motricity, as lipolytics, antiobesity agents,antidiabetics, antiglaucoma agents or cicatrizants, as inhibitors ofuterine contractions, as tocolytics for preventing or delaying prematurelabor, for the treatment and/or prophylaxis of dysmenorrhea, aspsychotropics or antidepressants, and for the treatment of urinaryincontinence.
 12. The compound of formula (I) as claimed in claim 2wherein R₂ represents an —SO₂(C₁-C₄)alkyl group or an —NHSO₂(C₁-C₄)alkylgroup, in the form of the base or of addition salts with acids, and inthe form of hydrates or of solvates.
 13. The compound as claimed inclaim 2 wherein R₃ is chosen from one of the following groups: an —X—R₄group, in which X and R₄ are as defined in claim 1, R₄ not representing,however, a hydrogen atom when X represents a bond or a —CH₂— group, aphenyl group optionally substituted by one to three groups chosen,independently of one another, from halogen atoms, (C₁-C₄)alkyl groupsand (C₁-C₄)alkoxy groups or fused with a dioxolane group, or a —CO—NR₈R₉group, in which R₈ is as defined in claim 1 and R₉ is chosen from one ofthe following groups: a (C₁-C₄)alkyl(C₁-C₄)alkoxy group, a group offormula —(CH₂)_(n)-A, where n is equal to 0, 1, 2, 3 or 4 and where Arepresents an indolyl group, a fluorenyl group or a phenyl groupsubstituted by one to three groups independently chosen from halogenatoms, hydroxyl groups and (C₁-C₄)alkyl groups, an —NH-phenyl group,where the phenyl group is optionally substituted by one to three groupschosen, independently of one another, from halogen atoms, hydroxylgroups and (C₁-C₄)alkyl groups, or a group of formula—CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n is equal to 0, 1, 2 or 3 and whereR₁₀ and R₁₁ are as defined in claim 1; in the form of the base or ofaddition salts with acids, and in the form of hydrates or of solvates.14. The compound as claimed in claim 3 wherein R₃ is chosen from one ofthe following groups: an —X—R₄ group, in which X and R₄ are as definedin claim 1, R₄ not representing, however, a hydrogen atom when Xrepresents a bond or a —CH₂— group, a phenyl group optionallysubstituted by one to three groups chosen, independently of one another,from halogen atoms, (C₁-C₄)alkyl groups and (C₁-C₄)alkoxy groups orfused with a dioxolane group, or a —CO—NR₈R₉ group, in which R₈ is asdefined in claim 1 and R₉ is chosen from one of the following groups: a(C₁-C₄)alkyl(C₁-C₄)alkoxy group, a group of formula —(CH₂)_(n)-A, wheren is equal to 0, 1, 2, 3 or 4 and where A represents an indolyl group, afluorenyl group or a phenyl group substituted by one to three groupsindependently chosen from halogen atoms, hydroxyl groups and(C₁-C₄)alkyl groups, an —NH-phenyl group, where the phenyl group isoptionally substituted by one to three groups chosen, independently ofone another, from halogen atoms, hydroxyl groups and (C₁-C₄)alkylgroups, or a group of formula —CH(R₁₀)—(CH₂)_(n)—COOR₁₁, where n isequal to 0, 1, 2 or 3 and where R₁₀ and R₁₁ are as defined in claim 1;in the form of the base or of addition salts with acids, and in the formof hydrates or of solvates.
 15. A pharmaceutical composition comprisinga compound of formula (I) as claimed in claim 2 or a pharmaceuticallyacceptable salt, a hydrate or a solvate of this compound, and at leastone pharmaceutically acceptable excipient.
 16. A pharmaceuticalcomposition comprising a compound of formula (I) as claimed in claim 3or a pharmaceutically acceptable salt, a hydrate or a solvate of thiscompound, and at least one pharmaceutically acceptable excipient.
 17. Apharmaceutical composition comprising a compound of formula (I) asclaimed in claim 4 or a pharmaceutically acceptable salt, a hydrate or asolvate of this compound, and at least one pharmaceutically acceptableexcipient.
 18. A pharmaceutical composition comprising a compound offormula (I) as claimed in claim 5 or a pharmaceutically acceptable salt,a hydrate or a solvate of this compound, and at least onepharmaceutically acceptable excipient.
 19. A pharmaceutical compositioncomprising a compound of formula (I) as claimed in claim 12 or apharmaceutically acceptable salt, a hydrate or a solvate of thiscompound, and at least one pharmaceutically acceptable excipient.
 20. Apharmaceutical composition comprising a compound of formula (I) asclaimed in claim 13 or a pharmaceutically acceptable salt, a hydrate ora solvate of this compound, and at least one pharmaceutically acceptableexcipient.
 21. A pharmaceutical composition comprising a compound offormula (I) as claimed in claim 14 or a pharmaceutically acceptablesalt, a hydrate or a solvate of this compound, and at least onepharmaceutically acceptable excipient.
 22. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 2. 23. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 3. 24. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 4. 25. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 5. 26. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 12. 27. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 13. 28. A method for the treatment ofdiseases in which β₃ receptors are implicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 14. 29. A method according to claim 22for the treatment of gastrointestinal diseases, such as inflammatorydiseases of the intestine, for example irritable bowel syndrome (IBS) orinflammatory bowel disease (IBD), as modulators of intestinal motricity,as lipolytics, antiobesity agents, antidiabetics, antiglaucoma agents orcicatrizants, as inhibitors of uterine contractions, as tocolytics forpreventing or delaying premature labor, for the treatment and/orprophylaxis of dysmenorrhea, as psychotropics or antidepressants, andfor the treatment of urinary incontinence.
 30. A method according toclaim 23 for the treatment of gastrointestinal diseases, such asinflammatory diseases of the intestine, for example irritable bowelsyndrome (IBS) or inflammatory bowel disease (IBD), as modulators ofintestinal motricity, as lipolytics, antiobesity agents, antidiabetics,antiglaucoma agents or cicatrizants, as inhibitors of uterinecontractions, as tocolytics for preventing or delaying premature labor,for the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 31. Amethod according to claim 24 for the treatment of gastrointestinaldiseases, such as inflammatory diseases of the intestine, for exampleirritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), asmodulators of intestinal motricity, as lipolytics, antiobesity agents,antidiabetics, antiglaucoma agents or cicatrizants, as inhibitors ofuterine contractions, as tocolytics for preventing or delaying prematurelabor, for the treatment and/or prophylaxis of dysmenorrhea, aspsychotropics or antidepressants, and for the treatment of urinaryincontinence.
 32. A method according to claim 25 for the treatment ofgastrointestinal diseases, such as inflammatory diseases of theintestine, for example irritable bowel syndrome (IBS) or inflammatorybowel disease (IBD), as modulators of intestinal motricity, aslipolytics, antiobesity agents, antidiabetics, antiglaucoma agents orcicatrizants, as inhibitors of uterine contractions, as tocolytics forpreventing or delaying premature labor, for the treatment and/orprophylaxis of dysmenorrhea, as psychotropics or antidepressants, andfor the treatment of urinary incontinence.
 33. A method according toclaim 26 for the treatment of gastrointestinal diseases, such asinflammatory diseases of the intestine, for example irritable bowelsyndrome (IBS) or inflammatory bowel disease (IBD), as modulators ofintestinal motricity, as lipolytics, antiobesity agents, antidiabetics,antiglaucoma agents or cicatrizants, as inhibitors of uterinecontractions, as tocolytics for preventing or delaying premature labor,for the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 34. Amethod according to claim 27 for the treatment of gastrointestinaldiseases, such as inflammatory diseases of the intestine, for exampleirritable bowel syndrome (IBS) or inflammatory bowel disease (IBD), asmodulators of intestinal motricity, as lipolytics, antiobesity agents,antidiabetics, antiglaucoma agents or cicatrizants, as inhibitors ofuterine contractions, as tocolytics for preventing or delaying prematurelabor, for the treatment and/or prophylaxis of dysmenorrhea, aspsychotropics or antidepressants, and for the treatment of urinaryincontinence.
 35. A method according to claim 28 for the treatment ofgastrointestinal diseases, such as inflammatory diseases of theintestine, for example irritable bowel syndrome (IBS) or inflammatorybowel disease (IBD), as modulators of intestinal motricity, aslipolytics, antiobesity agents, antidiabetics, antiglaucoma agents orcicatrizants, as inhibitors of uterine contractions, as tocolytics forpreventing or delaying premature labor, for the treatment and/orprophylaxis of dysmenorrhea, as psychotropics or antidepressants, andfor the treatment of urinary incontinence.